title: Increased brain transport and metabolism of acetate in hypoglycemia unawareness.
abstract: BACKGROUND
  Intensive insulin therapy reduces the risk for long-term complications in patients with type 1 diabetes mellitus (T1DM) but increases the risk for hypoglycemia-associated autonomic failure (HAAF), a syndrome that includes hypoglycemia unawareness and defective glucose counterregulation (reduced epinephrine and glucagon responses to hypoglycemia).
  
  
  OBJECTIVE
  The objective of the study was to address mechanisms underlying HAAF, we investigated whether nonglucose fuels such as acetate, a monocarboxylic acid (MCA), can support cerebral energetics during hypoglycemia in T1DM individuals with hypoglycemia unawareness.
  
  
  METHODS
  Magnetic resonance spectroscopy was used to measure brain transport and metabolism of [2-(13)C]acetate under hypoglycemic conditions.
  
  
  METHODS
  The study was conducted at the Yale Center for Clinical Investigation Hospital Research Unit, Yale Magnetic Resonance Research Center.
  
  
  METHODS
  T1DM participants with moderate to severe hypoglycemia unawareness (n = 7), T1DM controls without hypoglycemia unawareness (n = 5), and healthy nondiabetic controls (n = 10) participated in the study.
  
  
  METHODS
  Brain acetate concentrations, (13)C percent enrichment of glutamine and glutamate, and absolute rates of acetate metabolism were measured.
  
  
  RESULTS
  Absolute rates of acetate metabolism in the cerebral cortex were 1.5-fold higher among T1DM/unaware participants compared with both control groups during hypoglycemia (P = .001). Epinephrine levels of T1DM/unaware subjects were significantly lower than both control groups (P < .05). Epinephrine levels were inversely correlated with levels of cerebral acetate use across the entire study population (P < .01), suggesting a relationship between up-regulated brain MCA use and HAAF.
  
  
  CONCLUSIONS
  Increased MCA transport and metabolism among T1DM individuals with hypoglycemia unawareness may be a mechanism to supply the brain with nonglucose fuels during episodes of acute hypoglycemia and may contribute to the syndrome of hypoglycemia unawareness, independent of diabetes.
authors.affiliation: Department of Internal Medicine, Yale University School of Medicine, 300 Cedar Street, New Haven, Connecticut 06520, USA.
authors.forename: Barbara I
authors.initials: BI
authors.lastname: Gulanski
authors.forename: Henk M
authors.initials: HM
authors.lastname: De Feyter
authors.forename: Kathleen A
authors.initials: KA
authors.lastname: Page
authors.forename: Renata
authors.initials: R
authors.lastname: Belfort-DeAguiar
authors.forename: Graeme F
authors.initials: GF
authors.lastname: Mason
authors.forename: Douglas L
authors.initials: DL
authors.lastname: Rothman
authors.forename: Robert S
authors.initials: RS
authors.lastname: Sherwin
mesh_terms: D019342:Acetic Acid / Q000378:metabolism*; D000293:Adolescent; D000328:Adult; D001692:Biological Transport; D001786:Blood Glucose / Q000378:metabolism*; D001921:Brain / Q000378:metabolism*; D003922:Diabetes Mellitus, Type 1 / Q000188:drug therapy / Q000378:metabolism; D005260:Female; D006801:Humans; D007003:Hypoglycemia / Q000139:chemically induced / Q000378:metabolism*; D007004:Hypoglycemic Agents / Q000009:adverse effects* / Q000627:therapeutic use; D007328:Insulin / Q000009:adverse effects* / Q000627:therapeutic use; D008297:Male; D008875:Middle Aged; D054970:Pure Autonomic Failure / Q000139:chemically induced / Q000378:metabolism
chemical_list: D001786:Blood Glucose; D007004:Hypoglycemic Agents; D007328:Insulin; D019342:Acetic Acid